The purpose of this investigation is to assess the autonomic control mechanisms regulating airway smooth muscle tone and ion transport across respiratory epithelium. Using an isometric in situ tracheal muscle preparation and a recently developed in situ bronchial preparation, we will determine the pharmacological and physiological significance of alpha-adrenergic receptors in regulating airway smooth muscle (ASM) tone and the significance of autonomic neutral interactions in the augmentation and inhibition of respiratory smooth muscle response to histaminic stimulation. We will use a pharmacological method, which we recently developed, to produce selective neural cholinergic stimulation of airways and further determine if (1) respiratory mast cell secretion of mediator and (2) airway smooth muscle responses are augmented by physiological activation of cholinergic and alpha-adrenergic receptors. In a second series of studies, we will relate physiological and pharmacological studies of alpha-adrenergic, cholinergic and histamine responses and interactions in vivo to airway ASM responses obtained in organ bath preparations of ASM from the same animal. We will study the time course and viability of pharmacological and physiological autonomic responses in vitro. In prior studies, we have shown that tracheal muscle contains both Alpha 1 and Alpha 2-adrenergic receptor subtypes. These studies will permit us to assess the relevance in vitro preparations to the in situ response of ASM and permit us to assess the topographical distribution alpha-adrenergic receptor subtypes in airways. The response to selective Alpha 1-and Alpha 2-adrenergic agonists will be further studied and classified according to potency anc intrinsic activity in tracheal and bronchial smooth muscle. In a final series of experiments, we will employ electrophysiological techniques to study ion transport across tracheal epithelium. These studies will allow us to assess separately the physiological and pharmacological relevance of cholinergic, alpha 1-, and alpha 2-, and beta-adrenergic receptor stimulation on respiratory secretion in the major conducting airways of the lung. These investigations will further the understanding of autonomic control mechanisms in the regulation of bronchomotor tone and respiratory secretion and will suggest mechanisms for therapeutic intervention in human asthma and chronic bronchitis.